Mechanisms Controlling Sensitivity to Platinum Complexes: Role of p53 and DNA Mismatch Repair
Mechanisms Controlling Sensitivity to Platinum Complexes: Role of p53 and DNA Mismatch Repair
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DOI：
10.2174/1568009033333727
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发表时间：
2003-01-01
影响因子：
3
通讯作者：
Perego, P.
中科院分区：
文献类型：
--
作者：
Manic, S.;Gatti, L.;Perego, P.
尽管顺铂在治疗不同类型的肿瘤中是有效的，但对治疗的抗性是主要限制。在克服抗性机制的尝试中，已经做出了很大的努力来产生具有不同几何形状的化合物。目前，临床上最相关的化合物包括单核（i. e.奥沙利铂）以及多核铂络合物（i. e. BBR 3464）。细胞对铂络合物的反应机制尚未完全阐明。在影响这些药物的细胞敏感性的主要途径中，至少对于顺铂和BBR 3464，已经提出了p53的作用。我们的研究结果表明，奥沙利铂的细胞毒性也是通过该途径调节的。事实上，奥沙利铂的作用在表达突变型p53的肿瘤细胞中可能会降低。DNA错配修复系统似乎在调节细胞对顺铂的敏感性方面也是至关重要的，因为DNA错配修复的丧失导致对顺铂的低水平耐药性，而不是对奥沙利铂的耐药性。因此，铂化合物被赋予不同的能力，激活p53依赖性或独立的细胞凋亡的途径，并通过特定的细胞系统的差异识别可能是药物暴露后细胞命运（死亡/存活）的关键决定因素。需要进一步的分子研究，以更好地定义这些途径对临床相关铂络合物的细胞反应的精确贡献。对铂类药物敏感性的分子基础的完整理解有望为肿瘤治疗的优化提供有用的见解。
Although cisplatin is effective in the treatment of different types of tumors, resistance to treatment is a major limitation. In an attempt of overcoming resistance mechanisms, a large effort has been made to generate compounds with a different geometry. At present, the most clinically relevant compounds include mononuclear (i. e. oxaliplatin) as well as multinuclear platinum complexes (i. e. BBR 3464). The mechanisms of cellular response to platinum complexes have not been completely elucidated. Among the main pathways affecting cell sensitivity of these drugs a role for p53 has been proposed at least for cisplatin and BBR 3464. Our results indicate that, also in the case of oxaliplatin, cytotoxicity is modulated by this pathway. Indeed, the effect of oxaliplatin could be reduced in tumor cells expressing mutant p53. The DNA mismatch repair system also appears to be critical in regulating cellular sensitivity to cisplatin because the loss of DNA mismatch repair results in low level of resistance to cisplatin, but not to oxaliplatin. Thus, platinum compounds are endowed with differential capability to activate pathways of p53-dependent or independent apoptosis, and differential recognition by specific cellular systems is likely to be the critical determinant of the cell fate (death/survival) after drug exposure. Further molecular studies are required to better define the precise contribution of such pathways to the cellular responses of the clinically relevant platinum complexes. A complete understanding of the molecular basis of sensitivity to platinum drugs is expected to provide useful insights for the optimization of tumor treatment.